More than half the adult acute myeloid leukemia (AML) exhibits resistance to chemotherapy using anticancer agents, and thus, is refractory. Such refractory leukemia has poor prognosis, even if born marrow transplantation has been conducted. Thus, it is urgently required to develop a novel treatment method therefor. To date, in order to clarify a mechanism of the onset of refractory leukemia, the present inventors had conducted genomic analysis and the functional analysis of onset factors thereof, and had isolated a large number of onset-related factor groups. In particular, the inventors had conducted the pathological analysis of refractory leukemia involving an overexpression of the transcriptional factor EVIL and as a result of comprehensive gene expression analysis, they had identified an overexpression of α6-integrin (ITGA6) and β4 (ITGB4). It had been found that this ITGA6/B4 is highly expressed not only in leukemia involving an overexpression of EVI1, but also in a group of patients with leukemia relapse after completion of the treatment. This phenomenon is generally observed over the refractory leukemia as a whole. Moreover, it had also been identified that the overexpression of ITGA6/B4 contributes to the enhanced adhesion of leukemia cells to osteoblasts and laminin as an extracellular matrix, and further, to the achievement of resistance to various types of anticancer agents (Non Patent Literature 1).
The enhanced cell adhesion ability of leukemia cells is a phenomenon that has been well known as Cell Adhesion Mediated Drug Resistance (CAM-DR), and in recent years, a mechanism whereby leukemic stem cells (hereinafter referred to as “LSC”) take over a bone marrow niche (hereinafter referred to as “osteoblasts) for hematopoietic stem cells (hereinafter referred to as “HSC”) (which is adhesion involving utilization of a bone marrow niche environment), and achieve resistance to anticancer agents, has been revealed. An integrin family associated with adhesion of HSC to the bone marrow niche has is mainly VLA-4 (ITGA4/B1) (Non Patent Literature 2), but it has been found that LSC depends on ITGA6B4. Accordingly, it is considered that the development of a treatment method, which targets a specific adhesion molecule ITGA6/B4 that is associated with CAM-DR leading to incurability, would lead to the development of a method for effectively treating refractory leukemia, for which there have been no conventional treatment methods so far (Patent Literature 1).
An antibody capable of reacting against ITGA6B4 has been manufactured by Biogen IDEC MA, Inc., and has been reported in 2007. This antibody has been reported to have an ability to inhibit the growth of cells and inhibit adhesion of the cells to laminin (Patent Literature 2).
The present inventors have searched for an antigen (antibody) specific to cancer cells by a method for comprehensively isolating a human antibody, which targets many cancer cells, based on the Phage Display method (Patent Literature 3). As a result, ITGA6/B4 (antibody) has been included in the obtained 29 types of targets, and the validity of ITGA6/B4 as an antibody drug target has been proved also from another viewpoint (Non Patent Literature 3).
From the viewpoint of the side effects of a pharmaceutical product, since chemotherapeutic agents are not specific to cancer cells, but also exhibit effects on cells with activated cellular division, including normal cells, it has been conventionally very important to control administration of the agents. On the other hand, since molecular-targeted agents have been selectively designed to specific targeted molecules, these agents are characterized in that their side effects are reduced in comparison to the aforementioned chemotherapeutic agents. Antibodies are also molecular-targeted agents, and thus, when compared with enzyme inhibitors (kinase inhibitors) and the like, the specificity of such antibodies to targets has been improved. With such target specificity, antibody drugs are anticipated to have reduced side effects, but individual antibody drugs are observed to have characteristic side effects. It is considered that some side effects are caused by induction of immune responses such as ADCC (antibody-dependent cellular cytotoxicity) or CDC (complement-dependent cytotoxicity), which are derived from the properties of antibody molecules, and that some other side effects are caused by agonistic or antagonistic activities induced as a result of action on target molecules. Moreover, in recent years, antibody drugs have exhibited strong effects as a result of reinforced immune responses or drug modification. At the same time, however, considerable attention should be paid on the side effects of the antibody drugs.